PB1848: NGS AS A FUNDAMENTAL TOOL FOR THE DEVELOPMENT OF NEW TARGETED THERAPIES
Authors: P. Velarde, M. Sole, R. Zapata, E. Gil
Journal: HemaSphere (2022)

Background: Sequenced patients with Acute Mieloblastic Leukemia “AML” using second-generation sequencing “NGS” has notably increased in recent years. The development of targeted agents aims to achieve an improvement in clinical outcomes through personalized medicine. Aims: To analyze the frequency of mutations detected by NGS in adult patients with non-secondary AML diagnosed in a single center in the last 5 years. Disease profile at diagnosis and sample evolution in terms of overall survival (OS) and progression-free survival (PFS) were analyzed. Methods: Retrospective descriptive study. Data was collected through medical records review. Characteristics of 32 patients (≥18 years) with non-promyelocytic/non-secondary AML who received intensive chemotherapy (+/- Midostaurin and Gentuzumab Ozogamicin “GO”) were reported. Samples were analyzed by NGS in a different center. The gene panel includes 26 genes (ASXL1, CALR, CBL, CEBPA, DNMT3A, EZH2, FLT3, GATA2, IDH1, IDH2, JAK2, KIT, KRAS, MPL, MLL, NPM1, NRAS, PTPN11, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1, WT1). SPSS program (Statistical Package for Social Sciences) was used to analyze collected data. Results: 32 patients were reported: 41% male, 59% female. Patient characteristics and frequency of mutations detected by NGS are referred in Image 1. ELN risk; favorable (21%) intermediate (53%), adverse (21.9%). Induction regimen; Standard 3 + 7 (87.5%), 3 + 5 (3%), Vyxeos (CPX-351) (3%). FLT3+ (31%) received Midostaurin (day 8 to 21), CBF+ patients (3%) received GO. 37% were not trasplantated, 9% received Autologous Hematopoietic Stem Cell Transplantation, and 34% received Allogeneic Hematopoietic Stem Cell Transplantation. 77% achieved complete remission (CR) post-Induction and 12% were resistant. 28% achieved negative Minimal Residual Disease “MRD” and 53% remained positive MRD post-Induction. 25% patients relapsed once and 12.5% ​​twice. 42% patients were exitus. OS (global sample) was 56% median of 35 months 95% CI (26-44), PFS was 75% median of 43 months 95% CI (35-52). 100% of NMP1+/FLT3- patients achieved CR post-Induction compared to 80% NMP1+/FLT3+. OS was 62% in NPM1+, median time of 38 months 95% CI (20-57) compared to 54% in NPM1- patients, median time of 31.7 months IC 95% (22-40). Image:Summary/Conclusion: Our results in terms of frequency of mutations in patients remains very similar with previous published data: FLT3+ (28% in our sample compared to 25-39% reported), NMP1 (25% compared to 25-29%), DNMT3A (28% compared to 31%), IDH1 and IDH2 (6%, 15%) compared to 7% and 20%, NRAS (15% compared to 5-22%), WT1 (15% compared to 13%), ASXL1 (6% compared to 7%). NPM1 mutation is associated with higher CR rates and better OS. Our sample showed OS 62% vs 54% in NPM1+ compared to NPM1- patients proving published data, however statistical significance was not reached probably due to the insufficient sample. NPM1+/FLT3- genotype represents a favorable prognostic marker with higher CR rates and better OS. In fact, our sample showed 100% of CR in NPM1+/FLT3-ITD- patients compared to 80% of NMP1+/FLT3ITD+ patients. Due to NGS, patients can easily be stratified according to the ELN risk scale, however the limited number of patients was not enough to achieve significant results in terms of OS and PFS referred to the ELN. This study confirms the most frequent molecular alterations with should be mainly approached for development of new agents in order to achieve an improvement in clinical outcomes through personalized medicine.